Androgen deprivation therapies for metastatic prostate cancer are useful initially, but progression to androgen independence usually results in relapse within 2 years. Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival with this disease. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as pre-clinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents, however their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. Preliminary data that was generated as part of an R03 suggest that in vitro, omega-3 fatty acids are able to prevent the progression of hormone-dependent prostate cancer cells to the androgen-independent state. Our overall hypothesis is that essential polyunsaturated fatty acids are able to modulate genetic and epigenetic processes critical for prostate cancer progression to an androgen independent state, and that alteration in the balance between omega-3 fatty acids and omega-6 fatty acids results in changes to these processes that can be effectively exploited for the prevention of refractory prostate cancer. Based upon the results of our own studies and previously published reports from other laboratories, the specific hypothesis that we will address in this application is that omega-3 fatty acid modulation of processes that are linked to the Akt kinase pathway prevents prostate cancer progression to a state of hormone independence by precluding the ability of prostate cancer cells to survive during androgen deprivation and proliferate in an androgen-independent manner. We will address this hypotheses by performing the following Specific Aims: 1) To determine how essential polyunsaturated fatty acid (PUFA) regulation of NF-KB, COX-2 and PPAR transcription factors, all linked to the Akt kinase pathway, modulates processes critical for the progression to androgen independence;2) To determine the role of the mTOR kinase in modulating omega-3 fatty acid inhibition of prostate cancer progression to androgen independence;and finally 3) To investigate in vivo whether a diet enriched for omega-3 fatty acids can inhibit prostate cancer progression to a condition of hormone independence. Connecting the mechanisms by which omega- 3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. The impact of specific dietary components on prostate cancer progression likely depends on a host of genetic and epigenetic processes. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival.